Diazeniumdiolated compounds, pharmaceutical compositions, and method of treating cancer

Abstract

Disclosed is a method of treating cancer in a patient comprising administering to the patient an effective amount of a diazeniumdiolated (N 2 O 2 -containing) compound or a pharmaceutically acceptable salt thereof, wherein the cancer cell has an elevated level of reactive oxygen species (ROS) and/or a decreased level of one or more of PRX1, PRX6, and OGG1, compared to a normal cell of the same tissue or tissue type. An example of a diazeniumdiolated compound is Formula (I), wherein X and Q are defined herein. Also disclosed are diazeniumdiolated compounds, pharmaceutical compositions, and methods of use including enhancing the chemotherapeutic treatment of chemotherapeutic agents and high energy radiation.

The invention claimed is: 
     
       1. A method of treating non-small cell lung cancer in a patient comprising administering to the patient an effective amount of a diazeniumdiolated (N 2 O 2 -containing) compound of formula (Ia) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic, heteroaryl, and heteroaryl alkyl, each of which is optionally substituted with a substituent selected from the group consisting of halo, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino; and 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic, heteroaryl, heteroaryl alkyl, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino; 
 X 1  and X 2  are independently nitro or cyano; 
 n is 0, and 
 wherein the non-small cell lung cancer cell has an elevated level of reactive oxygen species (ROS) and/or a decreased level of one or more of PRX1, PRX6, and OGG1, compared to a normal cell of the same tissue or tissue type. 
 
     
     
       2. The method of  claim 1 , wherein R 1  is alkyl that is optionally substituted with a substituent selected from the group consisting of halo, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino. 
     
     
       3. The method of  claim 1 , wherein R 2 , R 3 , R 5 , and R 6  are each H. 
     
     
       4. The method of  claim 1 , wherein R 7  and R 9  are each H; and R 8  is H, alkyl, or alkoxy. 
     
     
       5. The method of  claim 1 , wherein the compound of formula (Ia) is 
       
         
           
           
               
               
           
         
       
     
     
       6. The method of  claim 1 , wherein the non-small cell lung cancer cell has an elevated level of reactive oxygen species (ROS) compared to a normal cell of the same tissue or tissue type. 
     
     
       7. The method of  claim 1 , wherein the non-small cell lung cancer cell has a decreased level of one or more of PRX1, PRX6, and OGG1 compared to a normal cell of the same tissue or tissue type. 
     
     
       8. The method of  claim 1 , wherein the non-small cell lung cancer cell has a peroxiredoxin 6 (PRX6) content less than about 10 units relative to the PRX6 content of a nonmalignant lung epithelial cell HPL1D which is 100 units. 
     
     
       9. The method of  claim 8 , wherein the non-small cell lung cancer cell has a PRX6 content less than about 5 units relative to the PRX6 content of a nonmalignant lung epithelial cell HPL1D which is 100 units. 
     
     
       10. The method of  claim 8 , wherein the non-small cell lung cancer cell further has a peroxiredoxin 1 (PRX1) content less than about 100 units relative to the PRX1 content of the nonmalignant lung epithelial HPL1D which is 100 units. 
     
     
       11. The method of  claim 1 , wherein the non-small cell lung cancer cell has an 8-oxo-dG DNA glycosylase (OGG1) content less than about 25 units relative to the OGG1 content of the nonmalignant lung epithelial HPL1D which is 100 units. 
     
     
       12. The method of  claim 1 , wherein the cancer is a non-small cell lung cancer (NSCLC) cell selected on the basis of quantification parameters established from studies of H1703, H1734, H1693, H1568, H1373, H2030, H2023, and H1944 cell lines. 
     
     
       13. The method of  claim 12 , wherein the quantification parameters include one or more of PRX1, PRX6, and OGG1 obtained from biopsies of the NSCLC tissue. 
     
     
       14. The method of  claim 1 , wherein the compound or a salt thereof is co-administered with a chemotherapeutic agent that produces reactive oxygen species (ROS) in the cancer cell or with a high energy radiation,
 wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine, daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mytomycin C, plicamycin, dactinomycin, paclitaxel, docetaxel, 5-fluorouracil, cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, methotrexate, fludarabine, clofarabine, cladribine, pentostatin, nelarabine, topotecan, irinotecan, azacitidine, decitabine, bortezomib, etoposide, teniposide, hydroxyurea, vincristine, vindesine, vinorelbine, vinblastine, imatinib, dasatinib, nilotinib, sorafenib, sunitinib, rituximab, cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab, carmustine, fotemustine, lomustine, L-Asparaginase, hexamethylmelamine, mitotane, thalidomide, lenalidomide, prednisone, dexamethasone, prednisolone, tamoxifen, raloxifene, leuprolide, bicaluatmide, granisetron, flutamide, letrozole, anastrozole, arsenic trioxide, tretinoin, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin, and any combination thereof. 
 
     
     
       15. The method of  claim 14 , wherein the chemotherapeutic agent is bortezomib or doxorubicin. 
     
     
       16. The method of  claim 1 , wherein the compound or salt is co-administered to the patient with a PARP inhibitor selected from the group consisting of iniparib, olaparib, ABT-888, and AG014699. 
     
     
       17. A method of enhancing chemotherapeutic treatment of cancer with a chemotherapeutic agent that produces reactive oxygen species (ROS) in the cancer cell or radiation treatment of non-small cell lung cancer, the method comprising administering an effective amount of a diazeniumdiolated compound of the formula (Ia): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic, heteroaryl, and heteroaryl alkyl, each of which is optionally substituted with a substituent selected from the group consisting of halo, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino; and 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic, heteroaryl, heteroaryl alkyl, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino; 
 X 1  and X 2  are independently nitro or cyano; and 
 n is 0; 
 
       or a pharmaceutically acceptable salt thereof,
 wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine, daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mytomycin C, plicamycin, dactinomycin, paclitaxel, docetaxel, 5-fluorouracil, cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, methotrexate, fludarabine, clofarabine, cladribine, pentostatin, nelarabine, topotecan, irinotecan, azacitidine, decitabine, bortezomib, etoposide, teniposide, hydroxyurea, vincristine, vindesine, vinorelbine, vinblastine, imatinib, dasatinib, nilotinib, sorafenib, sunitinib, rituximab, cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab, carmustine, fotemustine, lomustine, L-Asparaginase, hexamethylmelamine, mitotane, thalidomide, lenalidomide, prednisone, dexamethasone, prednisolone, tamoxifen, raloxifene, leuprolide, bicaluatmide, granisetron, flutamide, letrozole, anastrozole, arsenic trioxide, tretinoin, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin, and any combination thereof. 
 
     
     
       18. The method of  claim 17 , wherein the compound or salt is administered simultaneously with the chemotherapeutic treatment or radiation treatment, sequentially with chemotherapeutic treatment or radiation treatment, or cyclically with chemotherapeutic treatment or radiation treatment. 
     
     
       19. The method of  claim 18 , wherein the compound or salt is administered prior to the chemotherapeutic treatment or radiation treatment. 
     
     
       20. The method of  claim 18 , wherein the compound or salt is administered subsequent to the chemotherapeutic treatment or radiation treatment. 
     
     
       21. The method of  claim 17 , wherein R 1  is alkyl that is optionally substituted with a substituent selected from the group consisting of halo, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino. 
     
     
       22. The method of  claim 17 , wherein R 2 , R 3 , R 5 , and R 6  are each H. 
     
     
       23. The method of  claim 17 , wherein R 7  and R 9  are each H; and R 8  is H, alkyl, or alkoxy. 
     
     
       24. The method of  claim 17 , wherein the compound of formula (Ia) is 
       
         
           
           
               
               
           
         
       
     
     
       25. A compound of the formula (Ic): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic, heteroaryl, and heteroaryl alkyl, each of which is optionally substituted with a substituent selected from the group consisting of halo, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino; and 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, aryl alkyl, aryl, heterocyclic, heteroaryl, heteroaryl alkyl, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino; 
 X 1  and X 2  are independently nitro or cyano; 
 wherein at least one of X 1  and X 2  is cyano; 
 n is 0; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       26. The compound of  claim 25 , wherein R 1  is alkyl that is optionally substituted with a substituent selected from the group consisting of halo, OH, CN, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, aryloxy, thioalkoxy, nitro, sulfonato, formyl, acyl, acyloxy, carboxyl, mercapto, alkoxycarbonyl, alkoxycarbonyloxy, amido, amino, alkylamino, and dialkylamino. 
     
     
       27. The compound of  claim 25 , wherein R 2 , R 3 , R 5 , and R 6  are each H. 
     
     
       28. The compound of  claim 25 , wherein R 7  and R 9  are each H; and R 8  is H, alkyl, or alkoxy. 
     
     
       29. The compound of  claim 25 , wherein the compound of formula (Ic) is 
       
         
           
           
               
               
           
         
       
     
     
       30. A pharmaceutical composition comprising a compound or salt of  claim 25  and a pharmaceutically acceptable carrier. 
     
     
       31. A method of treating non-small cell lung cancer in a patient comprising administering an effective amount of a compound or salt of  claim 25  to the patient.